Serious morbidity and mortality in sickle cell anemia (SCA) is well-described and begins early in life with the onset of the physiologic decline of fetal hemoglobin (HbF). The BABY HUG trial showed that 20mg/kg/day of hydroxyurea therapy is safe, blunts the decline of HbF, and is clinically beneficial for very young infants and children with SCA. Nevertheless, children treated with hydroxyurea continued to develop acute complications and acquired end organ damage. Hydroxyurea therapy is now suggested to be offered to all very young children with sickle cell anemia, whether or not they have clinical symptoms. The BABY HUG trial established the safety and efficacy of fixed dosages of hydroxyurea therapy in this very young group of children; however, it is now paramount to define the optimal dosing regimen to maximize benefit. We believe that defining the clinical and hematologic impact of intensified dosages versus fixed dosing of hydroxyurea in this age group is crucial. The primary aims of this planning grant are to establish a multicenter infrastructure that will identify, enroll, and randomize very young children (9-36 months) using fixed vs. intensified dose HU in a single-blinded manner and to obtain prospective pilot data comparing the clinical and laboratory efficacy of intensified and fixed-dose HU. The HUGKISS trial is the next logical step to improve upon BABY HUG outcomes and advance the care of patients with SCA.